We propose to examine the influence of fat accumulation in the liver on ammonia detoxification in a study with the following specific aims: (1) A comparative study of the capacity of normal rats and rats with fatty livers to survive a challenge of ammonium acetate. (2) A comparative study of the effectiveness of urea cycle intermediates in protecting against ammonia toxicity in these rats. (3) Estimation of the activities of the mitochondrial and cytoplasmic portions of the urea cycle in suspended hepatocytes, liver slices, and the isolated perfused of these animals. (4) A comparison of ammonia detoxification in the fatty liver produced by the administration of orotic acid, 4-pentenoic acid, and choline deficiency. We have also obtained evidence for inhibition of the mitochondrial carbamoylphosphate synthetase by pyrimidines in intact hepatocytes. Since overproduction of orotic acid often accompanies hyperammonemia, we also propose: (5) An examination of the influence of pyrimidines on citrulline production and ureagenesis in the intact hepatocyte. These studies should provide insight into the relationship between fatty metamorphosis of the liver, hyperammonemia, the overproduction of orotic acid, and the capacity of the liver for ureagenesis.